Hacks and thwaks

Yesterday, for some bizarre, unknown reason known only to Yves Smith, I was accused of spouting PR for the pharmaceutical industry.  It appears that it goes against left of center dogma to say that the NIH does not just hand over perfect drug entities to the drug industry, already tested and bioavailable and efficacious, and that all the industry “R&D” divisions (well, what’s left of them) do is add a few finishing touches and charge everyone an arm and a leg for them.  Yes, that is what pharmas do.  They don’t really do research.  We just accept these gifts of government largess and when they arrive on our front door steps all glistening with ingenuity and brilliance, we stand around and marvel at them like they are alien creations.

Ok, the chemists can stop laughing now.  No, really, you’re going to hurt yourselves.

The truth is that NIH grants allow for some good science and many new discoveries.  But very rarely do they get to the stage where a new drug is delivered to a pharmaceutical company as a fully formed entity that requires no modification.  My experience (>20 years in the industry) is that NIH grants fund a lot of basic science on targets.  Then, if those targets (not drugs, protein targets) look interesting, they’re picked up by a pharmaceutical R&D, or more likely, several pharmaceutical R&Ds because the information is public, and all those different companies work on the target at the same time.  That’s how you get “me too” drugs. Just because someone beat you to market doesn’t mean you can trash all your hard work. Besides, your drug might actually be better.  It is strange that it is only in the pharmaceutical industry that “new and improved” is looked on as a bad thing.

Now, I am not going to argue that the pharmaceutical industry doesn’t charge an outrageous amount of money for new drugs these days.  And I won’t argue that they haven’t done much of anything to put new drugs on the market.  Or that they haven’t gone back into their old compound libraries  or that they reformulate things.  Sometimes, those reformulations are meaningful and sometimes they are not.

But I do know that research is expensive.  Ridiculously expensive.  That’s why big pharma has been cutting back on research as a counterintuitive business model.  That’s why there’s nothing coming out of the labs.  They are spending less money these days and they are relying on academic groups more often now.  The reasons are many but chief among them is that after having spent many billions of dollars on research, very few new drugs were approved by the FDA.  And that could be a result of higher safety standards that didn’t exist when the project was started or the constant mergers and acquisitions and bad management and the explosion in biology in the past couple of decades and the new and trendy things that snake oil salesmen corporate ladder climbers sold to their bosses as the next big thing that weren’t ready for prime time.  In fact, if Yves had been reading the posts I have written in the past several years on the pharmaceutical industry, or Derek Lowe at In the Pipeline has been writing (check the archives, Yves) or even someone like Anthony Nicholls at Openeye has been writing, she would have gotten a more complete picture of what is really going on.

What is really going on is that the big pharmas are going “weightless”.  They think they can exploit little start up companies and academic groups and turn those compounds into drugs.  And they want a cheap workforce.  I mean REALLY cheap.  Like $37K/year is their ideal top of the salary band for post docs who will never find a job in industry.  So they have been pushing this nonsense to the White House and Congress that what we need is more students who will sacrifice themselves to STEM professions and forget about having a stable job or family life because it is the patriotic thing to do.

Meanwhile, there really are academic groups that are trying to create new drugs.  They consist of former industry professionals who have taken incredibly steep cuts in their salaries and work in facilities where their resources are vastly reduced compared to their formerly corporate lab environments.  The pharma industry has them right where they want them, using their decades of expertise to cobble together drugs out of shoestrings and bubblegum.  And those dedicated scientists spend a lot of time applying for grants from the NIH but the money is very hard to come by and can’t pay for all the things and people they need to do their jobs.  These people are amazing and I can’t say enough good things about them.

But they are the exceptions, not the rules.  The rule is that the vast majority of NIH funded research provides germs of ideas.  They are hints of possibilities, a bunch of gel slides and some correlations.  I have been on many projects that started with a few interesting papers from NIH funded research.  We spend a lot of time on these shiny little nuggets setting up assays and crystallizing proteins and screening millions of compounds and synthesizing new compounds only to find out that the NIH funded studies did NOT have all of the answers.  The initial studies had only part of the answers and didn’t know about all of the other pathways and upregulation or the initial study was just off and the assays don’t work like they should and the project has to solve a different problem before it circles back to the original problem.  In the process, the industry research uncovered many aspects of the biology that the NIH scientists didn’t have the time, money or urgency to discover by themselves.  Many millions of dollars have been spent chasing NIH beginnings that ran into brick walls and had to be abandoned.  In any pharmaceutical company, there were dozens and dozens of these kinds of projects going on all at the same time.  Many projects are started but bloody few succeed and the vast majority of drugs that are produced from the germ of an idea that came out of an NIH study originated in the compound library of the pharmaceutical company itself.

Those are just the facts, Yves.  You can talk to anybody who has ever worked in pharma in the past 20 years and they will confirm this.  Yes, some remarkable things have come out of academia but very few of them  came directly from some academic lab untouched.  All of the other drugs were industry generated.

The reason why drugs are so expensive and are going to get more expensive is because more companies are abandoning their small molecule drug discovery efforts, because they couldn’t get approvals and recoup their investments before the patent clock expired, and are now moving into biologicals, the next big thing.  Oh sure, there will be some small molecule efforts in areas like oncology but this is due to a very cynical calculation on the part of the bean counters.  Oncology drugs are fast tracked and the safety profile is relaxed. People with death sentences on their heads are more than willing to become human guinea pigs and put up with a lot more toxicity than average non-sick people. They’re less picky about formulations.  Sure it would be great if the drug is oral and easily bioavailable but if you have to take it by IV, that’s OK too. If the drug extends life by even a few months, some families would consider that a success and they’d be willing to pay whatever the market wants.  And best of all, patients don’t complain and file class action lawsuits.  If the treatment succeeds, everyone is happy no matter how much the liver is shot.  If it fails, well, the patient was going to die anyway.  The relatives chalk it up to fate. The shareholders are happy.

Biologicals are a whole different animal with their own share of problems from humanizing mouse antibodies and aggregation problems to all kinds of new and different things that no one even knew about the cell.  It’s going to be interesting and very expensive.

The rest of the non-wealthy people will have to live with generics, which are bound to get more expensive.  Yves is smart enough to figure out why because she understands scarcity, supply and demand.  But these will be older, less efficacious drugs.  Well, the public put it’s foot down about “me too” and demanded a higher level of perfection than any small molecule drug is likely to ever deliver and this is what happens.  No more new small molecule drugs.

There are many facets to this problem.  Everyone sees the issue they are closest to.  If you only consult one “expert”, you only see one part of the problem.  There is no reason to distrust those of us former industry professionals who have a different version of events.  Believe me, we are not going to tell you a lot of flattering things about the pharmaceutical industry that stupidly laid off all of its expertise.  But unless you find out what is really going on and who is doing what with which resources and how successful those resources are, you can’t develop a complete picture of the landscape of this problem.  And more importantly, you can’t *solve* the problem. That smacks of a very unscientific approach to solving problems and, in the end, it doesn’t serve the patients or American citizens well at all.  In fact, not gathering as much information as you can from different sources is precisely what Big Pharma wants you to do.  It’s asymmetrical information at its best.  You only have one part of the picture and they just sit back and laugh at your righteous indignation while you rail against them.  How is this different from the finance industry?

By the way, I am no finance person and I didn’t much care for economics.  But I took the time to read books and ethnographies and visited wonky sites and read Yves and waded through all this money crap that interests me not even in the slightest.  And although I don’t know everything, I know much more than I did four years ago.  I know what motivates the bastards now and what incentives need to be changed to make the system function again.  That’s a positive step, right?

So, maybe closing your ears to differing points of view is not a good thing, Yves.  You’re not helping us beat this thing.  And that is something no pharma PR rep would ever say.


And now for some IKEA hacks!

This first one is from one of my new favorite YouTubers, goodbrowngravy, who despite being a white southern male with an accent, appears to be not the ignorant redneck that some lefties think all white southern men are.  (Do we condescend and stereotype much?  I think we do.)

Here’s goodbrowngravy’s IKEA hack of a Rast dresser into a campaign style side table.  Nice work!

And here is a hack of an Expedit unit turned into a stereo system from Apartmenttherapy.

Speaking of IKEA, if you are in the area tomorrow of the Elizabeth, NJ IKEA, you can drop off some badly needed items for the NYC/NJ survivors of Hurricane Sandy. IKEA is teaming up with the RedCross and other organizations to provide furniture and funds and also to collect items from customers who are shopping on Sunday. Check here for a list of items that would be much appreciated.  The collection will start at 11:00am.  And I really need a Rast…

25 Responses

  1. I hope, Yves reads this, Riverdaughter. You are totally correct that a lot of us with no personal interest in economics have taken to reading her blog in these crazy/depressing days to learn more about what we’re up against economically.

    And while I didn’t come here initially thinking that I’d learn a thing about the Pharmaceutical Industry, I’ve come to rely on The Confluence as a source for what’s going on there.

    She would do well to consider visiting here now and then too.

    • Heck, she doesn’t even need to read me. All she needs to do is expand her sources to those people who have actually done research in the pharmaceutical industry. It’s not that hard. There are hundreds of thousands of us who have the time to talk to her.

  2. I saw that too. Not knowing her, as I do not do; I can only speculate that since every major bussiness in her particular area of the economy is based upon nothing but organized deceit at every level . . . she assumes that organized bussiness in general is based upon organized deceit at every level. Otherwise, why would she be so suspicious of the offer of free knowledge and explanatory background from someone in the research-production side of a very different bussiness?

    Since she has a large reader-base, perhaps it is worth the effort to offer explanations directly to her readerbase via comments, rather than offer to give her explanations herself. Different individuals among her readership may have different individual suspicion levels and some of them may be more reachable than others. Perhaps even offering links to some of your articles in any further comments you care to post there ( if any) could give interested NaCap readers an opportunity to circle back and read your links for themselves.

    If skin is thick enough, and offendedness is not the issue, perhaps one can comment again and again and over again over time . . . to wear down reflexive opposition to getting your views and knowledge a fair measure of hearing and a due consideration.

    • You know, I’ve tried that in her comment threads. In some cases, she moderated me so the comment never got posted. The suspicion and distrust is so deep that even someone who is trying to help gets shut out.
      I don’t come from the finance side of pharma but I know what they’ve been up to. I’ve seen the mistakes they’ve made. And I’ve experienced how maddeningly difficult it is to do research.
      From what I can tell, Yves sources are connected to the NIH and FDA folks. She should be cautious about bias in that regard. More than that, we have seen that some of those people are utterly clueless about industrial research and overly confident about their own abilities without a lot to back that up.
      We’re just trying to get the message out. And if Yves had read anything of what I’ve written on the subject, she would have quickly discovered that I had already proposed alternatives to the present drug discovery problem, including having the government employ us directly at modest but reasonable salaries, moving us back to the Midwest where cost of living is cheaper and signing the patents over to the American people. Ultimately, something like that is going to have to happen because research cannot successfully operate on a quarter to quarter basis and scientists can’t afford to fund their own research. The ultimate goal should be to focus on long term investment into research. Private entities aren’t interested in that but that is what will ultimately bring down the cost of drugs.
      But she doesn’t want to talk to us. There are thousands of us out here who are dying for an opportunity to let the world know what is happening but Yves only wants to talk to her friends and stick her fingers in her ears to everyone else who has actually done research.
      She’s not the only one but I have to say that she is the biggest disappointment in this regard.

      • If Yves won’t hear it from you, might she hear it from Lambert Strether? Lambert Strether is a very respected co-blogger on Yves’s site. I notice in that thread that Lambert Strether posted a comment which said something like ” Hi RD!” a little downthread from your first comment. Was this an effort to signal
        Yves that your comments are trustworthy?

        In which case, what if Lambert Strether all on his own, without being asked, were to decide to write his own comments or even a whole guest-post about the deep divide between the financialists and the science-productionists in pharma, with links to your blogposts as being a trustworthy source? Assuming LS reads these TC threads over here, he might decide to do that very thing without being asked.

    • I’ll admit I also have come to assume reflexively “that organized business in general is based upon organized deceit at every level”. My conscious intellect recognizes that’s not always true, but I have acquired a “guilty until proven innocent” attitude toward every enterprise that isn’t a Federation starship. ;)

      • Well, they’re NOT “based upon organized deceit at every level” at the research level. This is incredibly frustrating and insulting to the thousands and thousands of researchers who poured their hearts and souls into their work. We can’t all work for academia and it wouldn’t pay the bills anyway. I can’t understand how people such as yourself fail to see how badly R&D has been used and abused by finance types. It boggles the mind how I can write post after post on the subject and yet you can actually type a comment that says essentially, “I don’t believe you. Everything you’ve said is a lie.”

        Ok, let’s assume I am lying about absolutely everything. How does that make your drugs cheaper or give you new more effective, safer drugs? What do YOU get out of rejecting everything I have been telling you? There must be a benefit to ignoring and writing off everything I have said as an exaggeration or a lie, right? Or else, why would you do it?

        So, what benefit do you derive from ignoring the expertise of the people who have actually been there?

        • I didn’t say I thought you were lying. I should have made that clearer. I reflexively assume that the barons of business are dishonest, though as I said, my conscious intellect knows that isn’t always true. In any event, I didn’t mean the serfs who do the actual work.

  3. I skimmed the article and I don’t see your name. Yves called you out personally?

  4. It pains me to see a falling-out between two of my favorite bloggers, Yves and RiverDaughter, perhaps the smartest women on the internet.

    And I’m very disappointed to see that Yves has succumbed to her high dollar NYC bubble, with her comment about $15k India medical tourism. It shows an incapacity to understand ordinary peoples’ very difficult financial circumstances when it comes to medical issues (ordinary people meaning, say, the lower 80% or 90% of the income distribution).

    And Yves comment mentioning NDAs (link to her comment) clearly shows Yves knows much less than she thinks she does about how/what/why Pharma R&D operates. Sad.

    I suggest RiverDaughter write a series of articles to be posted on Yves blog that would educate Yves and her readers on drug research.

    • I have written those posts. I could relink them. But I can’t make anyone read them or take their distrust down enough to actually believe them.
      Horse, water and all that stuff.

      • I’d recommend re-linking or re-posting, re-writing if necessary, etc; should be easy for you to do since you’ve done the first drafts already. Keep repeating the message; most people need multiple exposures to a topic to learn anything. You seem tough enough to ignore being called a PR hack, especially since you’re obviously not, and that should eventually sink in to apparently prejudiced people like Yves.

    • P.S. Correction: “… perhaps the smartest women people on the internet. ” (I meant to be complimentary; I apologise if it came across as sexist.)

  5. We have so many problems now related to availability of drugs. Once a drug becomes generic, almost 100% of marketshare is lost and soon the developing company stops making it, Once we’re left with only generics, production problems cause shortages of the drugs. We have gone long periods of time without Penicillin G, hydralazine, nubain, various anesthesia drugs, estrogens, birth control pills etc. The push to get generic drugs by breaking patents has driven the cost of drugs way up because big pharma needs to pay for research costs in a shorter period of time. Now the pharma has decided that they can magically develop drugs without research things can only get worse.

    • Now you’re talking. The drug industry is very, very broken right now. Whether you are of the opinion that government needs to step in and do something now or wait until there’s no other choice, the endpoint is pretty much the same. The last thing we need is for influential people to insist on righteous indignation when they only know part of the story.
      I really think the problem is that serious and deserves more thoughtful consideration.

    • Try asking for a tetanus shot. Doctors laugh in my face.

  6. The drug industry has been broken for a long time. Even though oncology drugs can get to market faster, the profit margin may or may not be there. They do have more efficacious drugs for some childhood cancers, but since target population is so small, they are not on the market for lack of profit. Hoerst Marion Roussel went bankrupt developing a drug for schizophrenia. The drug looked wonderful only on paper. It simply did not work. The government , the taxpayers, are paying premium rates for Medicare Part D. But none of that money is being used for research to find newer drugs. I am also not so sure that we haven’t run the table on the traditional drugs and as said biologicals and even nanotechnology are the future. The government is going to have to step in and do something. I often wonder if we shouldn’t socialize the pharmaceutical industry.

  7. Generics come with a whole other set of problems and to deal with those problems would result in an increase in the cost of those generics. Everything comes at a cost. There is no free lunch. New drugs are expensive to develop and produce (especially if manufacutrered in the Western world) but they offer prospects of treatments that are not currenty available. Generics offer a reduction in the cost of the status quo by virture of competition, however they offer no new treatments. Given where the overwhelming majority of production of genertic drugs currently occurs, the potential for economic fraud, and as a result, higher risks to the consumer is great. Both China and India operate two manufacutring lines, one for the Western market and one for the internal market. The level of quality and expense betweeen the two lines is enormous. The mere existence of the two manufacutring lines creates an oppotrunity and insentive for fraud that does not exist in markets where the approach is to have only one production line.

  8. Way off thread but . . . remembering Katiebird’s “Damn right I’m entitled!” made me think of rewriting Ronal Reagan’s classic “I paid for that microphone!” quote just a little bit. “I paid for that entitlement!”
    That will resonate in the brain of everyone who remembers that classic Reagan quote.

  9. I’ve often thought that the guys in early discovery / medicinal have too many incentives to push candidates down the pipeline whether they are truly promising or not. I can’t tell you how many drugs I’ve worked on, in the development end of the R&D spectrum, that turned out to be total crap. I remember a psoriasis drug that came to us as a “high potency” drug. Rather than use the fixed equipment in our pilot plant (because it was all way too big), we set up a high potency production lab to produce the clinical supply material in ten and twenty liter Chemglass reactors. Turns out, the shit was totally inert.

    We had many more drugs that started out with expected doses in the 100-200 mg range, and before long people were considering 1-2 gram doses. And then there was the drug for depression that ended up causing testicular atrophy. Fortunately, that was discovered in animals before entry into humans. Many of these issues would not have been discovered in medicinal under any circumstances. Still, I think tighter controls on what candidates get pushed down the pipeline would have avoided at least a few of these.

    None of the drugs I’ve worked on were discovered in government labs. In a few cases, the general family of compounds was first discovered in academia, but the structures of the actual candidates are very different by the time they get to us. Sometimes they have to be tweaked to improve bioavailability. Sometimes, they need to be tweaked to avoid testicular atrophy.

    And it’s not as if, when a drug shows up on our doorstep, we can just run it into the pilot plant and start spitting out clinical material. Medicinal chemists produce drugs by whatever means necessary. But seldom is a medicinal process even remotely suitable for production scale. We have to change the reagents, solvents, and overall process for safety and robustness reasons. That takes a lot of work, by a lot of people, and we don’t work for free. Just a singe clinical campaign will cost several million dollars alone … and that’s pennies when compared to the cost of an actual clinical trial. It’s expensive. It adds up. And although I do think the whole process of screening candidates could be made more efficient and cost effective, people like Yves really have no clue.

    • OMG! It’s ZombieSymmetry. You’re like a celebrity to me. I love your Kaizen Event/5S/CauseMap videos. Hysterical. At first, I thought that was just parody but I just spoke to someone from “Un Named Pharmaceuticals” who said that the efficiency experts had come to her former workplace and it’s all true. And now you can’t even order your own pipets. They’re standardized. I couldn’t believe it. One of the first things my supervisor had me do when I went to structural biology from drug design was try on a bunch of different pipets from different companies because you need to be able to make perfectly round bubble free microliter drops on a cover slip and then put a perfectly round bubble free microliter drop right on top of it. It’s difficult to do unless you have a pipet that you feel really comfortable with. But according to my source, you need to make a special request for your own pipets now. No more trying things out to see which one fits. She said it had gotten so bad that people in the lab have small areas taped on the floors and they needed to move items in and out of those spaces in a prescribed way. What is the point of that?? Real discovery doesn’t happen that way. Heck, my last hanging drops wouldn’t have crystallized if I’d had to follow everything by some lean protocol. The sucker crystallized at room temperature flying in the face of experience and literature references. We just happened to discover it because it was not put away when we were changing labs.
      Anyway, I digress.
      I think it would surprise people to know that some of our colleagues are quitting rather than put up with it.
      But back to the NIH vs industry, I too have seen a number of failures. Like the 5Ht2c agonist that was meant to be an anorectic but turned out to give the primates dangerous priapism. Or the CB1 antagonist that was also supposed to be for appetite control but made the patient suicidally depressed.
      I haven’t had too many projects that actually got to the development stage. One was an kinase project for oncology. But I’ve worked on gamma secretase (gotta worry about Notch), 5Ht1a (gotta worry about just about everything). In the last couple of years I worked, I optimized ADME on libraries I designed and the number of threshholds that have to be crossed now is getting to be insurmountable. hERG is becoming a big problem now. But when I look back on the first papers I had to start with on my biggest project, it’s almost laughable how much about that kinase wasn’t understood at the time the papers were first published in 2006. I’d know that binding site in the dark and I didn’t learn that from papers. I learned that from the structures that my lab partner and then later structures that I crystallized, and then plenty of staring at them for hours on end and playing with different functional groups and running many gigabytes of calculations. But those calculations are run on HPC clusters using software that costs millions of dollars a year to license. The proteins are relatively cheap to make from ecoli but purifying them and crystallizing them and sending them to the synchrotron for data collection, that’s very expensive. I can remember the last days I was there where the bean counters were harassing my boss about how many samples we were sending to APS. But sometimes the crystals don’t defract well or are too small or you think you got something in the loop on the way to the puck but it turns out to be empty. There is no room for error now. Such things are expensive. So, you need to cut back on your iterations and to think carefully about what experiments you can do and which ones will get you into trouble with the accountants.
      Research done right can be very expensive but I think the money guys have made it more so because it is less efficient now. We can’t learn from our mistakes because we aren’t allowed to make any.
      The NIH myth has a very sturdy foothold in the minds of the left blogosphere. The level of distrust is so deep that they can’t see that maybe the people at the NIH and FDA that they’re talking to might have a reason for dissing industrial research. Transitional medicine is all the rage right now, as is biologics and nanomedicine. And I wish them luck, I really do. But you and I have seen how the next big thing comes on the scene without all of the kinks worked out or generating so much data that we can’t quite wrap our heads around.
      In the meantime, the directors need to fill their pipeline quota for the year so they nominate bromo benzene or something equally stupid. We all sit around looking at it saying, “That fails about 4 out of 5 Lipinski rules. Gee, I hope it’s active.”
      Pressure, pressure, pressure. My blood pressure is almost normal now after several crazy years trying to avoid the ax. The environment is pure madness in the corporate lab theses days.

    • Some people without a clue know it and they look for a clue or at least accept one if it is offered to them for free. Other people without a clue about something outside their area of expertise think that the depth and breadth of knowledge they have withIN their area of expertise means their mind is a huge Clues Closet with all the clues they need. Such people can be frustratingly clueproof. How does one clue the clueproof?

      In this case, how does one sneak in knowledge and/or links about pharmaceutichemicological research into the NaCap threads before Yves Smith discovers it and removes it? Thereby giving some of her readers time to learn that stuff and/or save those links?

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